title: Systemic and cerebral exposure to and pharmacokinetics of flavonols and terpene lactones after dosing standardized Ginkgo biloba leaf extracts to rats via different routes of administration.
abstract: OBJECTIVE
  Flavonols and terpene lactones are putatively responsible for the properties of Ginkgo biloba leaf extracts that relate to prevention and treatment of cardiovascular disease and cerebral insufficiency. Here, we characterized rat systemic and cerebral exposure to these ginkgo compounds after dosing, as well as the compounds' pharmacokinetics.
  
  
  METHODS
  Rats received single or multiple doses of ShuXueNing injection (prepared from GBE50 for intravenous administration) or GBE50 (a standardized extract of G. biloba leaves for oral administration). Brain delivery of the ginkgo compounds was assessed with microdialysis. Various rat samples were analysed using liquid chromatography/mass spectrometry.
  
  
  RESULTS
  Slow terminal elimination features of the flavonols counterbalanced the influence of poor oral bioavailability on their systemic exposure levels, which also resulted in significant accumulation of the compounds in plasma during the subchronic treatment with ShuXueNing injection and GBE50. Unlike the flavonols, the terpene lactones had poor enterohepatic circulation due to their rapid renal excretion and unknown metabolism. The flavonol glycosides occurred as major forms in plasma after dosing with ShuXueNing injection, while the flavonol aglycone conjugates were predominant in plasma after dosing with GBE50. Cerebral exposure was negligible for the flavonols and low for the terpene lactones.
  
  
  CONCLUSIONS
  Unlike the significant systemic exposure levels, the levels of cerebral exposure to the flavonols and terpene lactones are low. The elimination kinetic differences between the two classes of ginkgo compounds influence their relative systemic exposure levels. The information gained is relevant to linking ginkgo administration to the medicinal effects.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Shanghai, China; Hainan Medical University, Haikou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Feifei
authors.initials: F
authors.lastname: Du
authors.forename: Xutao
authors.initials: X
authors.lastname: Ma
authors.forename: Chenchun
authors.initials: C
authors.lastname: Zhong
authors.forename: Xiuxue
authors.initials: X
authors.lastname: Li
authors.forename: Fengqing
authors.initials: F
authors.lastname: Wang
authors.forename: Nating
authors.initials: N
authors.lastname: Zhang
authors.forename: Chuan
authors.initials: C
authors.lastname: Li
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002853:Chromatography, Liquid; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000493:pharmacokinetics; D044948:Flavonols / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics*; D020441:Ginkgo biloba / Q000737:chemistry*; D006027:Glycosides / Q000008:administration & dosage / Q000493:pharmacokinetics; D007783:Lactones / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics*; D008297:Male; D013058:Mass Spectrometry; D017551:Microdialysis; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D018515:Plant Leaves; D051381:Rats; D017207:Rats, Sprague-Dawley; D013729:Terpenes / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D004365:Drugs, Chinese Herbal; D044948:Flavonols; D006027:Glycosides; D007783:Lactones; D010936:Plant Extracts; D013729:Terpenes; C578963:shuxuening
keywords: GBE50; Ginkgo biloba; PK markers; ShuXueNing injection; cerebral exposure; flavonols; pharmacokinetics; route of administration; systemic exposure; terpene lactones